ABSTRACT Neovascularization is a key feature of ischemic retinal diseases and the wet form of age-related macular degeneration (AMD), all leading causes of severe vision loss. Vascular endothelial growth factor (VEGF) inhibitors have transformed the treatment of these disorders. Currently, three anti-VEGF drugs are widely used in the USA for ophthalmological indications, bevacizumab, ranibizumab and aflibercept. Millions of patients have been treated with these drugs worldwide. After five-year treatment with these drugs, about half of neovascular AMD patients had good vision, i.e. visual acuity 20/40 or better, an outcome that would have been out of reach before anti-VEGF agents were available. However, in real-life clinical settings, many patients do not experience the same degree of benefit observed in clinical trials, in part because they receive fewer anti-VEGF injection. So, there is an urgent need to discover and identify novel long-acting VEGF inhibitors. We hypothesized that the ability to bind heparan sulfate proteoglycans in the vitreous may be a strategy to promote intraocular retention, ultimately leading to a reduced burden of intravitreal injections. We designed a series of VEGF receptor 1 variants and identified some with strong heparin-binding characteristics and ability to bind to the vitreous. Preliminary data indicate that some of our variants have longer duration and greater efficacy in animal models of intraocular neovascularization than current standard of care. Our proposal represents the first systematic attempt to exploit the functional diversity associated with heparin-affinity of a VEGF receptor. We anticipate that it will result in the discovery and development of more effective and durable VEGF inhibitors for intravitreal administration.